• PMID: 25915602
• Gene Name: TNF
• Condition: Celiac disease
• Association: TNFA promoter haplotypes associate with CD independently from HLA. We suggest that their evaluation might enhance the accuracy in estimating the CD genetic risk.
• Mutation: IFNG +874A>T (rs2430561) and TNFA(-1031T>C, rs1799964; -857C>T, rs1799724; -376G>A, rs1800750; -308G>A, rs1800629; -238G>A, rs361525)
• Population size: 511
• Population details: 511 (244 Celiac disease, 267 controls)
• Sex: Male, Female
• Infertility type: Male infertility, Female infertility
• Other associated phenotypes: Celiac disease

TNFA Haplotype Genetic Testing Improves HLA in Estimating the Risk of Celiac Disease in Children

Rossi E, Basso D, Zambon CF, Navaglia F, Greco E, Pelloso M, Artuso S, Padoan A, Pescarin M, Aita A, Bozzato D, Moz S, Cananzi M, Guariso G, Plebani M.

BACKGROUND: TNF-α and IFN-γ play a role in the development of mucosal damage in celiac disease (CD). Polymorphisms of TNFA and IFNG genes, as well as of the TNFRSF1A gene, encoding the TNF-α receptor 1, might underlie different inter-individual disease susceptibility over a common HLA risk background. The aims of this study were to ascertain whether five SNPs in the TNFA promoter (-1031T>C,-857C>T,-376G>A,-308G>A,-238G>A), sequence variants of the TNFRSF1A gene and IFNG +874A>T polymorphism are associated with CD in a HLA independent manner. METHODS: 511 children (244 CD, 267 controls) were genotyped for HLA, TNFA and INFG (Real Time PCR). TNFRSF1A variants were studied (DHPLC and sequence). RESULTS: Only the rare TNFA-1031C (OR=0.65, 95% CI:0.44-0.95), -857T (OR=0.42, 95% CI:0.27-0.65), -376A (OR=2.25, 95% CI:1.12-4.51) and -308A (OR=4.76, 95% CI:3.12-7.26) alleles were significantly associated with CD. One TNFRSF1A variant was identified (c.625+10A>G, rs1800693), but not associated with CD. The CD-correlated TNFA SNPs resulted in six haplotypes. Two haplotypes were control-associated (CCGG and TTGG) and three were CD-associated (CCAG, TCGA and CCGA). The seventeen inferred haplotype combinations were grouped (A to E) based on their frequencies among CD. Binary logistic regression analysis documented a strong association between CD and HLA (OR for intermediate risk haplotypes=178; 95% CI:24-1317; OR for high risk haplotypes=2752; 95% CI:287-26387), but also an HLA-independent correlation between CD and TNFA haplotype combination groups. The CD risk for patients carrying an intermediate risk HLA haplotype could be sub-stratified by TNFA haplotype combinations. CONCLUSION: TNFA promoter haplotypes associate with CD independently from HLA. We suggest that their evaluation might enhance the accuracy in estimating the CD genetic risk. FAU - Rossi, Elisa AU - Rossi E AD - Department of Medicine-DIMED, University of Padova, Padova, Italy. FAU - Basso, Daniela AU - Basso D AD - Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy. FAU - Zambon, Carlo-Federico AU - Zambon CF AD - Department of Medicine-DIMED, University of Padova, Padova, Italy. FAU - Navaglia, Filippo AU - Navaglia F AD - Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy. FAU - Greco, Eliana AU - Greco E AD - Department of Medicine-DIMED, University of Padova, Padova, Italy. FAU - Pelloso, Michela AU - Pelloso M AD - Department of Medicine-DIMED, University of Padova, Padova, Italy. FAU - Artuso, Serena AU - Artuso S AD - Unit of Pediatric Gastroenterology, Department of Women and Children's Health, University-Hospital of Padova, Padova, Italy. FAU - Padoan, Andrea AU - Padoan A AD - Department of Medicine-DIMED, University of Padova, Padova, Italy. FAU - Pescarin, Matilde AU - Pescarin M AD - Unit of Pediatric Gastroenterology, Department of Women and Children's Health, University-Hospital of Padova, Padova, Italy. FAU - Aita, Ada AU - Aita A AD - Department of Medicine-DIMED, University of Padova, Padova, Italy. FAU - Bozzato, Dania AU - Bozzato D AD - Department of Medicine-DIMED, University of Padova, Padova, Italy. FAU - Moz, Stefania AU - Moz S AD - Department of Medicine-DIMED, University of Padova, Padova, Italy. FAU - Cananzi, Mara AU - Cananzi M AD - Unit of Pediatric Gastroenterology, Department of Women and Children's Health, University-Hospital of Padova, Padova, Italy. FAU - Guariso, Graziella AU - Guariso G AD - Unit of Pediatric Gastroenterology, Department of Women and Children's Health, University-Hospital of Padova, Padova, Italy.